tbuckley/cabot-search huggingface dataset:
Explainable deep learning approach for extracting cognitive features from hand-drawn images of intersecting pentagons
Authors: Shinya Tasaki, Namhee Kim, Tim Truty, Ada Zhang, Aron S. Buchman, Melissa Lamar, David A. Bennett
Journal: npj Digital Medicine (2023)

Hand drawing, which requires multiple neural systems for planning and controlling sequential movements, is a useful cognitive test for older adults. However, the conventional visual assessment of these drawings only captures limited attributes and overlooks subtle details that could help track cognitive states. Here, we utilized a deep-learning model, PentaMind, to examine cognition-related features from hand-drawn images of intersecting pentagons. PentaMind, trained on 13,777 images from 3111 participants in three aging cohorts, explained 23.3% of the variance in the global cognitive scores, 1.92 times more than the conventional rating. This accuracy improvement was due to capturing additional drawing features associated with motor impairments and cerebrovascular pathologies. By systematically modifying the input images, we discovered several important drawing attributes for cognition, including line waviness. Our results demonstrate that deep learning models can extract novel drawing metrics to improve the assessment and monitoring of cognitive decline and dementia in older adults.
Long-read sequencing identifies a common transposition haplotype predisposing for CLCNKB deletions
Authors: Nikolai Tschernoster, Florian Erger, Stefan Kohl, Björn Reusch, Andrea Wenzel, Stephen Walsh, Holger Thiele, Christian Becker, Marek Franitza, Malte P. Bartram, Martin Kömhoff, Lena Schumacher, Christian Kukat, Tatiana Borodina, Claudia Quedenau, Peter Nürnberg, Markus M Rinschen, Jan H. Driller, Bjørn P. Pedersen, Karl P. Schlingmann, Bruno Hüttel, Detlef Bockenhauer, Bodo Beck, Janine Altmüller
Journal: Genome Medicine (2023)

Long-read sequencing is increasingly used to uncover structural variants in the human genome, both functionally neutral and deleterious. Structural variants occur more frequently in regions with a high homology or repetitive segments, and one rearrangement may predispose to additional events. Bartter syndrome type 3 (BS 3) is a monogenic tubulopathy caused by deleterious variants in the chloride channel gene CLCNKB, a high proportion of these being large gene deletions. Multiplex ligation-dependent probe amplification, the current diagnostic gold standard for this type of mutation, will indicate a simple homozygous gene deletion in biallelic deletion carriers. However, since the phenotypic spectrum of BS 3 is broad even among biallelic deletion carriers, we undertook a more detailed analysis of precise breakpoint regions and genomic structure. Structural variants in 32 BS 3 patients from 29 families and one BS4b patient with CLCNKB deletions were investigated using long-read and synthetic long-read sequencing, as well as targeted long-read sequencing approaches. We report a ~3 kb duplication of 3'-UTR CLCNKB material transposed to the corresponding locus of the neighbouring CLCNKA gene, also found on ~50 % of alleles in healthy control individuals. This previously unknown common haplotype is significantly enriched in our cohort of patients with CLCNKB deletions (45 of 51 alleles with haplotype information, 2.2 kb and 3.0 kb transposition taken together, p=9.16×10-9). Breakpoint coordinates for the CLCNKB deletion were identifiable in 28 patients, with three being compound heterozygous. In total, eight different alleles were found, one of them a complex rearrangement with three breakpoint regions. Two patients had different CLCNKA/CLCNKB hybrid genes encoding a predicted CLCNKA/CLCNKB hybrid protein with likely residual function. The presence of multiple different deletion alleles in our cohort suggests that large CLCNKB gene deletions originated from many independently recurring genomic events clustered in a few hot spots. The uncovered associated sequence transposition haplotype apparently predisposes to these additional events. The spectrum of CLCNKB deletion alleles is broader than expected and likely still incomplete, but represents an obvious candidate for future genotype/phenotype association studies. We suggest a sensitive and cost-efficient approach, consisting of indirect sequence capture and long-read sequencing, to analyse disease-relevant structural variant hotspots in general.
PB2094: APPLICATION OF WHOLE-GENOME SEQUENCING FOR COPY NUMBER ABNORMALITY IN MULTIPLE MYELOMA
Authors: Jiali LI, Fu LI, Xixi Xiang, Jun Rao, Sha Zhou, Song Dong, Shijia Lin, Hongyun Liu, Yunjing Zeng, XI Zhang, LI Gao
Journal: HemaSphere (2023)

Topic: 14. Myeloma and other monoclonal gammopathies - Clinical Background: Copy number abnormalities (CAA) is an important prognosis factor for multiple myeloma (MM). The detection rate of existing detection methods is low and the chromosomal variation cannot be obtained comprehensively. LeukoPrint is a novel shallow whole-genome sequencing (sWGS) based approach to profile CNA may make up for the deficiencies of traditional detection techniques and improve the detection rate of chromosome variation. Aims: To observe the clinical application of sWGS in detecting chromosome copy number variation in patients with newly diagnosed multiple myeloma. Methods: A total of 131 patients with newly diagnosed multiple myeloma were enrolled in this study to compare the effectiveness of detection techniques among sWGS, Karyotyping, flurescence in situ hybridization (FISH). Karyotyping and FISH were performed by conventional approaches. CNA was detected by sWGS in genomic DNA from bone marrow aspiration samples and CD138+ enriched plasma cells as well as in plasma cfDNA. Risk stratification was performed following the Mayo Stratification of Myeloma and Risk-adapted Therapy (mSMART) criteria. Results: In this study, CNA events were identified by sWGS in 75.6% patients, while the positive rate of CNA detected by karyotyping and FISH was 7.8% and 43.7%, respectively. The most frequently mutational CNA peak region were amp(1q21),del(1p),del(6q), del(8p21.2), del(13q14),del(14q) and del(16p). The concordance rate between sWGS and FISH in detecting the four conventional loci (1q21 gain, 13q14 del, 13q14.3 del, and 17p13 del) was 80.2%. Comparing to the conventional approaches, sWGS provided new CNA information for 75.6% of the patients, and changed the risk stratification for 19.1% of patients according to mSMART criteria. sWGS showed good consistency the CNA detection between bone marrow and plasma cfDNA of 15 patients. Conclusion: sWGS is superior to conventional approaches when used for CNA testing, the practice of this method maybe improves prognostic stratification of MM patients and the clinical significance of some variation remains to be studied. Keywords: Multiple myeloma
We need a universally endorsed definition of a pandemic for the Pandemic Accord to be effective
Authors: Noor Shakfeh, Fifa A Rahman, Katri Bertram
Journal: BMJ (2023)

For the Pandemic Accord to be effective, member states must urgently focus negotiations to define its scope, including its definition of “pandemic,” and ensure the definition avoids the pitfalls of past mistakes, argue Noor Shakfeh, Fifa Rahman, and Katri Bertram
Clinical decision support and electronic interventions to improve care quality in chronic liver diseases and cirrhosis
Authors: Jin Ge, Valy Fontil, Sara Ackerman, Mark J. Pletcher, Jennifer C. Lai
Journal: Hepatology (2023)

Significant quality gaps exist in the management of chronic liver diseases and cirrhosis. Clinical decision support systems—information-driven tools based in and launched from the electronic health record—are attractive and potentially scalable prospective interventions that could help standardize clinical care in hepatology. Yet, clinical decision support systems have had a mixed record in clinical medicine due to issues with interoperability and compatibility with clinical workflows. In this review, we discuss the conceptual origins of clinical decision support systems, existing applications in liver diseases, issues and challenges with implementation, and emerging strategies to improve their integration in hepatology care.
Uptake of Genetic Research Results and Patient-Reported Outcomes With Return of Results Incorporating Web-Based Predisclosure Education
Authors: Madison Kilbride, Brian L. Egleston, Wendy K. Chung, Olufunmilayo Olopade, Kara N. Maxwell, Payal Shah, Jane E. Churpek, Linda Fleisher, Mary Beth Terry, Dominique Fetzer, Jill Bennett Gaieski, Jessica Bulafka, Aileen Espinal, Kelsey Karpink, Sarah Walser, Davone Singleton, Monica Palese, Ilona Siljander, Amanda Brandt, Dana Clark, Carrie Koval, Julia Wynn, Jessica M. Long, Danielle McKenna, Jacquelyn Powers, Sarah Nielsen, Susan M. Domchek, Katherine L. Nathanson, Angela R. Bradbury
Journal: Journal of Clinical Oncology (2023)

We developed a web-based education intervention as an alternative to predisclosure education with a genetic counselor (GC) to reduce participant burden and provider costs with return of genetic research results.
P1617: A PHASE 1 STUDY TO EVALUATE THE PHARMACOKINETICS, SAFETY AND TOLERABILITY OF A PEGYLATED-RECOMBINANT HUMAN COAGULATION FACTOR VIII-FC FUSION PROTEIN WITH HALF-LIFE IN PATIENTS WITH SEVERE HEMOPHILIA A
Authors: Feng Xue, Yun Chen Chen, Jing Sun, Shuxia Guo, Qing Wen, Chongyuan Xu, Renchi Yang
Journal: HemaSphere (2023)

Topic: 33. Bleeding disorders (congenital and acquired) Background: Replacement therapy with Factor VIII (FVIII) products in severe hemophilia A (HA) necessitates multiple doses of FVIII products weekly to sustain a > 1% FVIII trough activity due to their short half-life. FRSW117 is a PEGylated FVIII-Fc fusion protein engineered to prolong its half-life, maintain adequate FVIII levels and improve therapeutic effect. Aims: To assess the pharmacokinetics, safety/tolerability, and immunogenicity of FRSW117 in patients with severe HA. Methods: In this first-in-human, open label, single dose, self-controlled study, 13 males aged 12 to 65 years who had been previously treated patients with severe hemophilia A were enrolled to receive ADVATE® followed by FRSW117. The doses were at 25 IU/kg (N=6, S1 group) with an interval of 4-day wash-out period; or at 50 IU/kg (N=7, S2 group) with 6 days apart, followed by a 4-week follow-up after FRSW117 injection. All patients provided written informed consents. The protocol was approved by each site’s IEC/IRB. Results: The maximum concentration (Cmax) and area under the curve (AUC0-t) of FⅧ activity increased in a dose-dependent manner (Figure 1). The geometric mean elimination half-life of FRSW117 exceeded twice that of ADVATE® (30.928 hours vs. 13.668 hours in S1; 30.801 hours vs. 14.007 hours in S2) (Table 1). The average time of FVIII activity to 5% is 101.527 hours in S1 and 138.145 hours in S2. The time of FVIII activity to 1% in both groups surpassed 168 hours (7 days), with S1 being 176.769 hours and S2 being 206.253 hours.No FⅧ inhibitors were detected and no hypersensitivity or anaphylaxis were reported. No serious adverse events or ≥ Grade 3 adverse events were occurred. No spontaneous bleeding requiring intervention was needed within 9 days after treatment with FRSW117. Summary/Conclusion: The pharmacokinetic characteristics of FRSW117 supported a potential weekly treatment interval. It also displayed favorable safety/tolerability and immunogenicity profiles. (ClinicalTrials.gov identifier: NCT04864743)Keywords: Factor VIII, Pharmacokinetic, Clinical trial, Hemophilia A
P1556: EVALUATION OF THE USEFULNESS OF INTERFERON-GAMMA RELEASE ASSAY FOR THE DETECTION OF LATENT MYCOBACTERIUM TUBERCULOSIS INFECTIONS IN PATIENTS WHO UNDERWENT HEMATOPOIETIC STEM CELL TRANSPLANTATION
Authors: Yoengjoon Lee, Seonyang Park, Sungnam Lim
Journal: HemaSphere (2023)

Topic: 30. Infections in hematology (incl. supportive care/therapy) Background: Tuberculosis (TB) is still a major global public health problem. The likelihood of developing the active disease is much higher in frail patients, such as those with hematopoietic stem cell transplantation (HSCT). Patients undergoing HSCT have severe and prolonged immunodeficiency due to underlying hematologic malignancies, chemo- and immunosuppressive therapy, and graft-versus-host disease, and are generally considered to be at higher risk for active TB or reactivation of latent TB infections. Aims: The aim of this study was to evaluate the occurrence of active TB in patients who received a QuantiFERON test for the detection of latent TB infection. Methods: This is a retrospective observational cohort study, including all adult patients (>18 years old) with hematopoietic malignancies who underwent HSCT. In total, 201 patients who received an interferon-gamma release assay and underwent auto- or allogeneic hematopoietic stem cell transplantation between September 2010 and December 2021 were recruited to determine the usefulness of latent TB infection screening tests. Results: A total of 201 patients, 96 (47.8%) autologous and 105 (52.5%) allogeneic stem cell transplants, underwent QuantiFERON test screening: 148 (51.0%) were negative, 17 (5.9%) indeterminate, and 36 (12.4%) positive. Most of the enrolled patients were male (58.7%) with a median age of 54 years old (range, 19 ~ 69 years old). The most common hematologic malignancy affecting patients before HSCT was acute myeloid leukemia (36.6%), followed by multiple myeloma (14.2%), non-Hodgkin lymphoma (13.9%), and acute lymphoblastic leukemia (12.4%). The QuantiFERON screening test was performed within one month before HSCT. There was no difference in test positive rates between men and women. However, the positive rate was statistically significantly higher in elderly patients (p=0.001). Only 20% of the patients whose test was QuantiFERON test positive took isoniazid prophylaxis, and none of them progressed to active TB over a median follow-up period of 40.4 months. Active TB recurrence did not occur even in 80% of QuantiFERON test-positive who did not take isoniazid, also. Summary/Conclusion: In conclusion, 12.4% of our HSCT population had latent TB infection, only 20% of them received isoniazid prophylaxis. There were no cases of active TB progression in a cohort of 201 patients who underwent HSCT from 2010 to 2021. Keywords: Tuberculosis, Hematopoietic cell transplantation, Interferon gamma
‘Slicing’ glioblastoma drivers with the Swiss cheese model
Authors: Oriana Y. Teran Pumar, Justin D. Lathia, Dionysios C. Watson, Defne Bayik
Journal: Trends in cancer (2023)

The Swiss cheese model is used to assess risks and explain accidents in a variety of industries. This model can be applied to dissect the homeostatic mechanisms whose cumulative dysregulation contributes to disease states, including cancer. Using glioblastoma (GBM) as an exemplar, we discuss how specific protumorigenic mechanisms collectively drive disease by affecting genomic integrity, epigenetic regulation, metabolic homeostasis, and antitumor immunity. We further highlight how host factors, such as hormonal differences and aging, impact this process, and the interplay between these 'system failures' that enable tumor progression and foster therapeutic resistance. Finally, we examine therapies that consider the interactions between these elements, which may comprise more effective approaches given the multifaceted protumorigenic mechanisms that drive GBM.
Gene expression and RNA splicing explain large proportions of the heritability for complex traits in cattle
Authors: Ruidong Xiang, Lingzhao Fang, Shuli Liu, Iona M. Macleod, Zhiqian Liu, Edmond J. Breen, Yahui Gao, George E. Liu, Albert Tenesa, Brett A. Mason, Amanda J. Chamberlain, Naomi R. Wray, Michael E. Goddard
Journal: Cell Genomics (2023)

Many quantitative trait loci (QTLs) are in non-coding regions. Therefore, QTLs are assumed to affect gene regulation. Gene expression and RNA splicing are primary steps of transcription, so DNA variants changing gene expression (eVariants) or RNA splicing (sVariants) are expected to significantly affect phenotypes. We quantify the contribution of eVariants and sVariants detected from 16 tissues (n = 4,725) to 37 traits of ∼120,000 cattle (average magnitude of genetic correlation between traits = 0.13). Analyzed in Bayesian mixture models, averaged across 37 traits, cis and trans eVariants and sVariants detected from 16 tissues jointly explain 69.2% (SE = 0.5%) of heritability, 44% more than expected from the same number of random variants. This 69.2% includes an average of 24% from trans e-/sVariants (14% more than expected). Averaged across 56 lipidomic traits, multi-tissue cis and trans e-/sVariants also explain 71.5% (SE = 0.3%) of heritability, demonstrating the essential role of proximal and distal regulatory variants in shaping mammalian phenotypes.
Unraveling dynamically encoded latent transcriptomic patterns in pancreatic cancer cells by topic modeling
Authors: Yichen Zhang, Mohammadali (Sam) Khalilitousi, Yongjin P. Park
Journal: Cell Genomics (2023)

Building a comprehensive topic model has become an important research tool in single-cell genomics. With a topic model, we can decompose and ascertain distinctive cell topics shared across multiple cells, and the gene programs implicated by each topic can later serve as a predictive model in translational studies. Here, we present a Bayesian topic model that can uncover short-term RNA velocity patterns from a plethora of spliced and unspliced single-cell RNA-sequencing (RNA-seq) counts. We showed that modeling both types of RNA counts can improve robustness in statistical estimation and can reveal new aspects of dynamic changes that can be missed in static analysis. We showcase that our modeling framework can be used to identify statistically significant dynamic gene programs in pancreatic cancer data. Our results discovered that seven dynamic gene programs (topics) are highly correlated with cancer prognosis and generally enrich immune cell types and pathways.
Comprehensive single-cell genome analysis at nucleotide resolution using the PTA Analysis Toolbox
Authors: Sjors Middelkamp, Freek Manders, Flavia Peci, Markus J. van Roosmalen, Diego Montiel González, Eline J.M. Bertrums, Inge van der Werf, Lucca L.M. Derks, Niels M. Groenen, Mark Verheul, Laurianne Trabut, Cayetano Pleguezuelos-Manzano, Arianne M. Brandsma, Evangelia Antoniou, Dirk Reinhardt, Marc Bierings, Mirjam E. Belderbos, Ruben van Boxtel
Journal: Cell Genomics (2023)

Detection of somatic mutations in single cells has been severely hampered by technical limitations of whole-genome amplification. Novel technologies including primary template-directed amplification (PTA) significantly improved the accuracy of single-cell whole-genome sequencing (WGS) but still generate hundreds of artifacts per amplification reaction. We developed a comprehensive bioinformatic workflow, called the PTA Analysis Toolbox (PTATO), to accurately detect single base substitutions, insertions-deletions (indels), and structural variants in PTA-based WGS data. PTATO includes a machine learning approach and filtering based on recurrence to distinguish PTA artifacts from true mutations with high sensitivity (up to 90%), outperforming existing bioinformatic approaches. Using PTATO, we demonstrate that hematopoietic stem cells of patients with Fanconi anemia, which cannot be analyzed using regular WGS, have normal somatic single base substitution burdens but increased numbers of deletions. Our results show that PTATO enables studying somatic mutagenesis in the genomes of single cells with unprecedented sensitivity and accuracy.
PB2362: THE EFFECT OF BODY MASS INDEX (BMI) ON THE PROGNOSIS OF DLBCL PATIENTS TREATED WITH R-CHOP: A REAL WORLD MOROCCAN EXPERIENCE
Authors: Imane Ait el Filali, El Mehdi Mahtat, Elmaachi Nora, Selim Jennane, Hicham el Maaroufi, Doghmi Kamal
Journal: HemaSphere (2023)

Topic: 19. Aggressive Non-Hodgkin lymphoma - Clinical Background: The correlation between body mass index (BMI) and outcome of diffuse large B-cell lymphoma (DLBCL) is still debated in some studies. To clarify this relationship, we performed this study to examine the overall survival (OS) and progression-free survival (PFS) of DLBCL patients classified as overweight (BMI between 25 and <30kg/m2), obese (BMI of 30kg/m2 or more), underweight (BMI less than 18.5kg/m2), or normal weight (BMI between 18.5 and <25kg/m2). Aims: We retrospectively compared the outcomes of DLBCL patients treated with R-CHOP at our center according to BMI. Methods: We conducted a retrospective analysis of moroccan patients diagnosed with DLBCL and treated with R-CHOP from January 2010 to January 2021. The analysis only included patients with a calculated BMI. Demographic, prognostic, and therapeutic information was collected, Survival outcomes were analyzed using the summary hazard ratio (HR) and a 95% confidence interval (CI). Results: In the study, 140 subjects were included, and their age, performance score, international prognostic index, B-symptoms, and extranodal involvement were similar and comparable between the two groups. The analysis showed that the overall survival (OS) of the overweight group was better than that of the normal weight group. However, no association was found in obese patients. Similarly, neither obesity nor overweight significantly impacted progression-free survival (PFS) in DLBCL. However, underweight patients had worse OS and PFS than the normal weight group. Summary/Conclusion: In DLBCL, patients who are overweight have a better survival rate compared to those who are of normal weight, whereas underweight patients have a poorer survival rate. Keywords: DLBCL, Prognostic factor, Rituximab
PB1905: REAL-WORLD EXPERIENCE OF LOW-DOSE VENETOCLAX WITH AZACITIDINE FOR UNFIT AML PATIENTS(≥60Y) WITH LOW LEUKOCYTE COUNT
Authors: Wenjian Wei, Siyuan Cui, Yuping Si, Guodong MA
Journal: HemaSphere (2023)

Topic: 4. Acute myeloid leukemia - Clinical Background: The combination of venetoclax and hypomethylating agentscombination(HMA) therapy is very common for the treatment of older/unfit patients with AML,however,in the real world，most Chinese patients can not well tolerate venetoclax of standard dose,especially older/unfit patients with low leukocyte count.In this group of patients,We have tried to use low-dose venetoclax. Aims: To explore the efficacy and safety of low-dose venetoclax combined with azacitidine induction in the treatment of older/unfit patients with acute myeloid leukemia with low leukocyte count. Methods: Retrospective analysis of 25 untreated patients with acute myeloid leukemia with low leukocyte count who used low-dose venetoclax(50mg d1,100mg d2,200mg d3-d7/14/28)combined with azacitidine chemotherapy.To analysis the proportion of the incidence rate of CR+CRi, infections, bleeding, the number of blood products infusion and the median time of recovery of neutrophil count. Results: Of all 25 patients, 9 patients used venetoclax for 28 days, 14 patients used venetoclax for 14 days, and 2 patients used venetoclax for 7 days.The patients with 28 days of medication had the highest remission rate(P＜0.05）,the remission rate of patients treated for 14 days is slightly lower.Two patients who were treated for 7 days continuously, one of whom was infected and controlled, and one died of infection.The incidence rate of CR and CRi in patients was higher after 28 days of treatment than after 14 days of treatment (36% vs.56%,p＜0.05).The incidence rate of CR and CRi in patients after 7 days was 4%. Summary/Conclusion: In previously unifit AML patients(≥60Y) with low leukocyte count,overall survival was longer and the incidence of remission was higher among patients who received low-dose venetoclax with azacitidine for 14 days or 14 days than those who were treated for 7days. Real-world experience of low-dose venetoclax with azacitidine for unfit AML patients(≥60Y) with low leukocyte count Wei Wenjian1,Si Yuping1,Ma Guodong1, Cui Siyuan2* 1Shandong University of Traditional Chinese Medicine 2Affiliated Hospital of Shandong University of Traditional Chinese Medicin Keywords：venetoclax, azacitidine,AML, CR,CRi Keywords: Azacitidine, Acute myeloid leukemia, Venetoclax, Complete remission